According to the American Cancer Society survey, about 1.7 million Americans will be diagnosed with cancer and about 609,640 Americans are expected to die of cancer this year alone (American Cancer Society, Cancer Facts & Figures (2018)). Cancer metastasis is responsible for a vast majority of cancer-related deaths (Nicolo, R., et al., Annu Rev of Pathol: Mechanisms of disease, 13: 117-140 (2017)). Metastasis is the development of secondary malignant growths in a site in the body distant from the primary site of the cancer.
Metastatic disease is the end stage of extremely inefficient processes that entails overcoming multiple physiological barriers. Evidence from preclinical and clinical settings suggests that dissemination of malignant cells is an early process in cancer progression (Husemann, Y., et al., Cancer Cell, 13:58-68 (2008)). However, the majority of disseminated cells are either eliminated in circulation or remain dormant in distant organs including the bone marrow, while very few cells eventually develop successful metastasis (Husemann, Y., et al., Cancer Cell, 13:58-68 (2008); Nguyen, D., et al., Nat Rev Cancer, 9:274-284 (2009); Klein, C. A., Nat Rev Cancer, 9:302-312 (2009)). Therefore, the mechanism by which disseminated cells go on to establish successful metastasis is of utmost importance. S. Paget's ‘seed and soil’ hypothesis (Paget, S., Cancer Metastat Rev, 8:98-101 (1989)) for metastasis was a key milestone in cancer research that determined the direction of subsequent studies. Isaiah J. Fidler and others provided an unequivocal confirmation of the concept suggesting that some organs were more conducive than others for disseminated tumor cells ‘seed’ to grow (Nguyen, D., et al., Nat Rev Cancer, 9:274-284 (2009); Fidler, I. J. and Kripke, M. L., Cancer Res, 38:2651-2660 (1978); Fidler, I. J. and Kripke, M. L., Science, 197:893-895 (1977)). Advanced studies in recent decades reframed the ‘seed and soil’ concept in a modern context by which successful metastases require that developing malignant cells eliminate anti-tumor responses, a small subset of (disseminating) cells—‘seed’—undergo epithelial-mesenchymal transition (EMT) leading to cancer stem cell (CSC) phenotype and remotely generate a supportive microenvironment—‘soil’— in distant tissues (Soundararaj an, R., et al., Sci Rep, 5:11766 (2015); Grunert, S., et al., Nat Rev Mol Cell Biol, 4:657-665 (2003)). It is also accepted that successful colonization in distant organs requires disseminated tumors to revert back to epithelial phenotype via mesenchymal-epithelial transition (MET) to promote tumor cell proliferation (Tsai, et al., Cancer Cell, 22:725-736 (2012)). Furthermore, a dynamic and reversible transition between EMT and MET state has been shown to be a critical process in driving squamous cell carcinoma metastasis (Tsai, et al., Cancer Cell, 22:725-736 (2012)). Consistent with this notion, EMT signature alone fails to predict metastasis in majority of malignancies (Soundararajan, R., et al., Sci Rep, 5:11766 (2015); Tan, et al., EMBO Mol Med, 6:1279-1293 (2014); Chikaishi, Y., et al., Anticancer Res, 31:4451-4456 (2011)).
Emerging evidence suggests that tumor-infiltrated immune cells (mainly from myeloid origin) differentiate into cells that promote tumor growth and invasion in addition to their immunosuppressive role (Marvel, D. and Gabrilovich, D. I., J Clin Invest, 125:3356-3362 (2015); Condamine, T., et al., Annu Rev Med, 66:97-110 (2015)). Although myeloid-derived suppressor cells (MDSC) were initially identified in cancer patients and mouse models due to their potent immunesuppressive activity, they are now being implicated in the promotion of tumor metastasis by participating in the formation of pre-metastatic niches, angiogenesis and invasion (Condamine, T., et al., Annu Rev Med, 66:97-110 (2015)). MDSCs are a heterogeneous population of immature myeloid cells that include monocytic (mMDSC) and granulocytic (gMDSC) subsets both of which have been shown to be immunesuppressive. However, the majority of current studies do not separate the two groups of MDSCs.
The majority of well-known chemotherapies are hindered by induction of MDSCs, and T-cell suppression (Ding, Z., et al., Oncoimmunology, 8: e954471, (2014), Gargett, T., et al., Clin Transl Immunology, 5(12): e119 (2016)). There is a great need for drugs that can assist in boosting T-cell production, prevent cancer metastasis, and prepare the host body to accommodate adjuvant cancer therapeutics.
Therefore, it is an object of the invention to provide compositions and methods for inhibiting metastasis.
It is another object of the invention to provide compositions and methods for treating metastatic cancer.